Fragment- and structure-based drug discovery for developing therapeutic agents targeting the DNA Damage Response

• Published in: Progress in biophysics and molecular biology Vol. 163; pp. 130 - 142
• Main Authors: Wilson, David M., Deacon, Ashley M., Duncton, Matthew A.J., Pellicena, Patricia, Georgiadis, Millie M., Yeh, Andrew P., Arvai, Andrew S., Moiani, Davide, Tainer, John A., Das, Debanu
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2021; Elsevier
• Subjects: APE1; Cancer therapeutics; Crystallography, X-Ray; DNA Damage; DNA damage Response; DNA Repair; Drug Discovery; FEN1; Fragment-based drug discovery; MRE11; Pharmaceutical Preparations; Structure-based drug discovery; X-ray crystallography; X-ray crystallography; FEN1; MRE11; Cancer therapeutics; APE1; Fragment-based drug discovery; Structure-based drug discovery; DNA repair; DNA damage Response
• ISSN: 0079-6107; 1873-1732
• DOI: 10.1016/j.pbiomolbio.2020.10.005

Cancer will directly affect the lives of over one-third of the population. The DNA Damage Response (DDR) is an intricate system involving damage recognition, cell cycle regulation, DNA repair, and ultimately cell fate determination, playing a central role in cancer etiology and therapy. Two primary therapeutic approaches involving DDR targeting include: combinatorial treatments employing anticancer genotoxic agents; and synthetic lethality, exploiting a sporadic DDR defect as a mechanism for cancer-specific therapy. Whereas, many DDR proteins have proven “undruggable”, Fragment- and Structure-Based Drug Discovery (FBDD, SBDD) have advanced therapeutic agent identification and development. FBDD has led to 4 (with ∼50 more drugs under preclinical and clinical development), while SBDD is estimated to have contributed to the development of >200, FDA-approved medicines. Protein X-ray crystallography-based fragment library screening, especially for elusive or “undruggable” targets, allows for simultaneous generation of hits plus details of protein-ligand interactions and binding sites (orthosteric or allosteric) that inform chemical tractability, downstream biology, and intellectual property. Using a novel high-throughput crystallography-based fragment library screening platform, we screened five diverse proteins, yielding hit rates of ∼2–8% and crystal structures from ∼1.8 to 3.2 Å. We consider current FBDD/SBDD methods and some exemplary results of efforts to design inhibitors against the DDR nucleases meiotic recombination 11 (MRE11, a.k.a., MRE11A), apurinic/apyrimidinic endonuclease 1 (APE1, a.k.a., APEX1), and flap endonuclease 1 (FEN1).